Angiogenesis is the generation of new blood vessels in a tissue or organ. Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development, and formation of the corpus luteum, endometrium and placenta.
Capillary blood vessels are composed of endothelial cells and pericytes, surrounded by a basement membrane. Angiogenesis begins with the erosion of the basement membrane by enzymes released from endothelial cells and leukocytes. Endothelial cells, lining the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating a new blood vessel.
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. For example, FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor). However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer. The growth factor receptor protein tyrosine kinase inhibitor can inhibit the above phosphorylation process and will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth.
Uncontrolled angiogenesis is a hallmark of cancer. In 1971, Dr. Judah Folkman proposed that tumor growth is dependent upon angiogenesis. See, e.g., Folkman, New England Journal of Medicine, 285:1182-86 (1971). According to Dr. Folkman, a tumor can only grow to a certain size without the growth of additional blood vessels to nourish the tumor. In its simplest terms, this proposition states: that “once tumor ‘take’ has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor.” Tumor ‘take’ is currently understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters volume, and not exceeding a few million cells, can survive on existing host microvessels.
It has been shown that tumors can be treated by inhibiting angiogenesis rather than inhibiting proliferation of the tumor cells themselves. Angiogenesis has been associated with a number of different types of cancer, including solid tumors and blood-borne tumors. Solid tumors with which angiogenesis has been associated include, but are not limited to, rhabdomyosarcomas, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Angiogenesis also has been linked with breast cancer, prostate cancer, lung cancer, and colon cancer. Angiogenesis is also associated with blood-borne tumors, such as leukemias, lymphomas, multiple myelomas, and any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver and spleen. It is believed too that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia and lymphoma tumors and multiple myeloma diseases.
Angiogenesis plays a major role in the metastasis of cancer. If this angiogenic activity could be repressed or eliminated, then the tumor, although present, would not grow. In the disease state, prevention of angiogenesis could overt the damage caused by the invasion of the new micro vascular system. Therapies directed at control of angiogenic processes could lead to the abrogation or mitigation of these diseases.
Among others, the studies on the inhibition of angiogenesis with the inhibitors for FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor) become more and more mature.
Moreover, a large body of literature implicates FGF (Fibroblast growth factor), VEGF (Vascular endothelial growth factor) and PDGF (Platelet-derived growth factor) in the induction or persistence of fibrosis (Levitzki, Cytokine & Growth Factor Rev, 2004, 15(4): 229-35; Strutz et al., Kidney Int, 2000, 57: 1521-38; Strutz et al., 2003, Springer Semin Immunopathol, 24: 459-76; Rice et al., 1999, Amer J Pathol, 155(1): 213-221; Broekelmann et al., 1991, Proc Nat Acad Sci, 88: 6642-6; Wynn, 2004, Nat Rev Immunol, 4(8): 583-94).
FGF1/FGF2-deficient mice show dramatically decreased liver fibrosis after chronic carbon tetrachloride (CC14) exposure (Yu et al., 2003, Am J Pathol, 163(4): 1653-62). FGF expression is increased in human renal interstitial fibrosis where it strongly correlates with interstitial scarring (Strutz et al., 2000, Kidney Intl, 57:1521-38) as well as in a model of experimental lung fibrosis (Barrios et al., 1997, Am J Physiol, 273 (2 Pt 1): L451-8), again lending credence to the idea that fibrosis in various tissues has a common basis.
The increased expression of VEGF/VEGFR is relevant to a great number of microvascular and pulmonary fibrosis (X.-M Ou et al. International Immunopharmacology 9 (2009): 70-79), and the VEGFR-2 inhibitor, SU5416, alleviates the fibrous tissue pathology of the belomycin-induced pulmonary fibrosis in mice.
Inhibition of PDGF attenuates both liver fibrosis and lung fibrosis in experimental models, suggesting fibrosis in different organs may have a common origin (Borkham-Kamphorst et al. 2004, Biochem Biophys Res Commun; Rice et al., 1999, Amer J Pathol, 155(1): 213-221).
Finally, TGFβ stimulates production of extracellular matrix proteins including fibronectin and collagens and is believed to play an important role in fibrosis in many tissues (Leask et al., 2004, FaSEB J 18(7): 816-27; Bartram et al., 2004, Chest 125(2): 754-65; Strutz et al., 2003, Springer Semin Immunopathol, 24: 459-76; Wynn, 2004, Nat Rev Immunol, 4(8): 583-94). Inhibitors of TGFβ production and signaling pathways are active in a number of fibrosis animal models (Wang et al., 2002, Exp Lung Res, 28:405-17; Laping, 2003, Curr Opin Pharmacol, 3(2): 204-8).
As summarized above, several growth factors are upregulated in fibrosis and the inhibition of a single factor seems to reduce the severity of fibrosis in the fibrosis models.
Pulmonary fibrosis is one of the four largest respiratory diseases. It is caused by several pathogenic factors, and is a severe pathological condition faced or experienced by the pulmonary patient. Since the cause of disease is complex, there is lacking an efficient way to treat it clinically. Besides Pirfenidone, there is no other medicament for treating the pulmonary fibrosis all over the world. Pirfenidone has the following structure and has the anti-fibrosis function by inhibiting the TGFβ signal pathway.

Currently, there is no small molecule tyrosine kinase inhibitor for treating tumor and fibrosis on the market. Intedanib, a compound that is now being fastest developed, is in Phase III clinical trial. Its structure is shown as above.
The object of the present invention is to develop a medicament having both the good anti-tumor activity and the good anti-fibrosis function, and therefore a small molecule tyrosine kinase inhibitor was found.